Emerging Role and Potential Therapeutic Application of TRIM Proteins in Cardiovascular Diseases

Many tripartite motif (TRIM) proteins self-associate, forming dimers and higher order complexes. For example, dimers of TRIM5α, a host factor that restricts retrovirus infection, assemble into higher order arrays on the surface of the viral capsid, resulting in an increase in avidity. Here we show that the higher order association of different TRIM proteins exhibits a wide range of efficiencies. Homologous association (self-association) was more efficient than the heterologous association of different TRIM proteins, indicating that specificity determinants of higher order self-association exist. To investigate the structural determinants of higher order self-association, we studied TRIM mutants and chimeras. These studies revealed the following: 1) the RING domain contributes to the efficiency of higher order self-association, which enhances the binding of TRIM5α to the human immunodeficiency virus (HIV-1) capsid; 2) the RING and B-box 2 domains work together as a homologous unit to promote higher order association of dimers; 3) dimerization is probably required for efficient higher order self-association; 4) the Linker 2 region contributes to higher order self-association, independently of effects of Linker 2 changes on TRIM dimerization; and 5) for efficiently self-associating TRIM proteins, the B30.2(SPRY) domain is not required for higher order self-association. These results support a model in which both ends of the core TRIM dimer (RING-B-box 2 at one end and Linker 2 at the other) contribute to the formation of higher order arrays.

Deregulation of ubiquitin-mediated degradation of oncogene products or tumor suppressors appears to be implicated in the genesis of carcinomas, according to new clinical findings. Conferring to recent research, some members of the tripartite motif (TRIM) proteins (a subfamily of the RING type E3 ubiquitin ligases) act as significant carcinogenesis regulators. Intracellular signaling, development, apoptosis, protein quality control, innate immunity, autophagy, and carcinogenesis are all regulated by TRIM family proteins, the majority of which have E3 ubiquitin ligase activity. The expression of TRIMs in tumors is likely to be related to the formation and/or progression of the disease, and TRIM expression could be used to predict cancer prognosis. Breast cancer is the most common malignancy in women and also the leading cause of death. TRIM family proteins have unique, vital activities, and their dysregulation, such as TRIM 21, promotes breast cancer, according to growing evidence. Many TRIM proteins have been identified as important cancer biomarkers, with decreased or elevated levels of expression. TRIM29 functions as a hypoxia-induced tumor suppressor gene, revealing a new molecular mechanism for ATM-dependent breast cancer suppression. In breast cancer cells, the TRIM28-TWIST1-EMT axis exists, and TRIM28 enhances breast cancer metastasis by stabilizing TWIST1, and thereby increasing epithelial-tomesenchymal transition. Interestingly, many TRIM proteins are involved in the control of p53, and many TRIM proteins are likewise regulated by p53, according to current research. Furthermore, TRIMs linked to specific tumors may aid in the creation of innovative TRIM-targeted cancer treatments. This review focuses on TRIM proteins that are involved in tumor development, progression, and are of clinical significance in breast cancer.

Tripartite motif (TRIM)7 is an E3 ubiquitin ligase that was first identified through its interaction with glycogenin-1 (GN1), the autoglucosyltransferase that initiates glycogen biosynthesis. A growing body of evidence indicates that TRIM7 plays an important role in cancer development, viral pathogenesis, and atherosclerosis and, thus, represents a potential therapeutic target. TRIM family proteins share a multidomain architecture with a conserved N-terminal TRIM and a variable C-terminal domain. Human TRIM7 contains the canonical TRIM motif and a B30.2 domain at the C terminus. To contribute to the understanding of the mechanism of action of TRIM7, we solved the X-ray crystal structure of its B30.2 domain (TRIM7B30.2) in two crystal forms at resolutions of 1.6 Å and 1.8 Å. TRIM7B30.2 exhibits the typical B30.2 domain fold, consisting of two antiparallel β-sheets of seven and six strands, arranged as a distorted β-sandwich. Furthermore, two long loops partially cover the concave face of the β-sandwich defined by the β-sheet of six strands, thus forming a positively charged cavity. We used sequence conservation and mutational analyses to provide evidence of a putative binding interface for GN1. These studies showed that Leu423, Ser499, and Cys501 of TRIM7B30.2 and the C-terminal 33 amino acids of GN1 are critical for this binding interaction. Molecular dynamics simulations also revealed that hydrogen bond and hydrophobic interactions play a major role in the stability of a modeled TRIM7B30.2-GN1 C-terminal peptide complex. These data provide useful information that could be used to target this interaction for the development of potential therapeutic agents.

Background: Prediabetes are often characterized by various measurements of elevated but non-diabetic glucose values, including impaired fasting glucose (IFG), 2-hour impaired glucose tolerance (IGT), and glycosylated hemoglobin A1c (HbA1c), and represent increased risk for cardiovascular disease (CVD) morbidity and mortality. However, it remains unclear how each glucose measurement differs in their abilities to predict risk for CVD outcomes. Currently, the World Health Organization (WHO) and the American Diabetes Association (ADA) also differ in their IFG definitions, and there has been debate as to which definition best predicts future CVD risk. Objectives: In this systematic review and meta-analysis, we sought to evaluate the prognostic value of different cut-points of non-diabetic glucose measurements (IFG, IGT, and HbA1c) for predicting CVD morbidity and mortality in individuals at increased risk. Methods: We searched the MEDLINE, PubMed, Embase, Clinicaltrials.gov, World Health Organization (WHO) International Clinical Trials Registry Platform, and Cochrane database. We searched prospective cohort studies in adults without diabetes aged 18 years or older, or control groups in clinical trials, with a minimum follow-up of 3 years. We included studies that reported an association between any of the glucose measurements with CVD morbidity, including non-fatal myocardial infarction, non-fatal stroke, peripheral artery disease, a composite measure of any CVD outcomes, and CVD mortality. Retrospective cohort studies will only be investigated if there are not at least two prospective cohort studies for a given outcome. Data from eligible studies were pooled to synthesize results for each glucose measurement. Random effect model was used to calculate pooled hazard ratio or relative risk data. Results: We screened over 4,000 abstracts and identified 170 eligible prospective cohort studies with 2,826,296 individuals, with a mean follow-up of 10.2 years. Compared to individuals with normal glycaemia, individuals with IFG defined by the WHO criteria had 1.11 and 1.21 times increased risk for CVD morbidity and mortality, respectively. There was no significant increase in risk among those with IFG diagnosed by the ADA criteria compared to those with normal glycaemia. Compared to those with normal glycaemia, individuals with IGT had 1.15 and 1.24 times higher risk for CVD morbidity and mortality, respectively. HbA1c as low as 5.5% was associated with an increased risk of CVD outcomes. Conclusions: The WHO criteria for IFG seems to be a better predictor of CVD outcomes than the ADA criteria. The current criteria for IGT is a slightly strong predictor for CVD events and mortality than IFG. HbA1c levels as low as 5.5% could be used as a predictor for adverse health outcomes in non-diabetic individuals.

The Tripartite motif (TRIM) protein family, which contains over 80 members in human sapiens, is the largest subfamily of the RING-type E3 ubiquitin ligase family. It is implicated in regulating various cellular functions, including cell cycle process, autophagy, and immune response. The dysfunction of TRIMs may lead to numerous diseases, such as systemic lupus erythematosus (SLE). Lots of studies in recent years have demonstrated that many TRIM proteins exert antiviral roles. TRIM proteins could affect viral replication by regulating the signaling pathways of antiviral innate immune responses. Besides, TRIM proteins can directly target viral components, which can lead to the degradation or functional inhibition of viral protein through degradative or non-degradative mechanisms and consequently interrupt the viral lifecycle. However, new evidence suggests that some viruses may manipulate TRIM proteins for their replication. Here, we summarize the latest discoveries on the interactions between TRIM protein and virus, especially TRIM proteins’ role in the signaling pathway of antiviral innate immune response and the direct “game” between them.

The tripartite motif (TRIM) proteins have been intensively studied as essential modulators in various biological processes, especially in regulating a wide range of signaling pathways involved in immune responses. Most TRIM proteins have E3 ubiquitin ligase activity, mediating polyubiquitination of target proteins. Emerging evidence demonstrates that TRIM proteins play important roles in innate immunity by regulating pattern recognition receptors, vital adaptor proteins, kinases, and transcription factors in innate immune signaling pathways. Additionally, the critical roles of TRIM proteins in adaptive immunity, especially in T cell development and activation, are increasingly appreciated. In this review, we aim to summarize the studies on TRIMs in both innate and adaptive immunity, focusing on their E3 ubiquitin ligase functions in pattern recognition receptor signaling pathways and T cell functions, shedding light on the developing new strategies for modulating innate and adaptive immune responses against invading pathogens and avoiding autoimmunity.

Tripartite motif (TRIM) proteins, comprising a family of over 100 members with conserved motifs, exhibit diverse biological functions. Several TRIM proteins influence viral infections through direct antiviral mechanisms or by regulating host antiviral innate immune responses. To identify TRIM proteins modulating hepatitis B virus (HBV) replication, we assessed 45 human TRIMs in HBV-transfected HepG2 cells. Our study revealed that ectopic expression of 12 TRIM proteins significantly reduced HBV RNA and subsequent capsid-associated DNA levels. Notably, TRIM65 uniquely downregulated viral pregenomic (pg) RNA in an HBV-promoter-specific manner, suggesting a targeted antiviral effect. Mechanistically, TRIM65 inhibited HBV replication primarily at the transcriptional level via its E3 ubiquitin ligase activity and intact B-box domain. Though HNF4α emerged as a potential TRIM65 substrate, disrupting its binding site on the HBV genome did not completely abolish TRIM65's antiviral effect. In addition, neither HBx expression nor cellular MAVS signaling was essential to TRIM65-mediated regulation of HBV transcription. Furthermore, CRISPR-mediated knock-out of TRIM65 in the HepG2-NTCP cells boosted HBV infection, validating its endogenous role. These findings underscore TRIM proteins' capacity to inhibit HBV transcription and highlight TRIM65's pivotal role in this process.

With their modular structure and E3 ubiquitin ligase activity, Tripartite motif (TRIM) proteins interact with a wide range of cellular and viral substrates. This review summarizes how they have emerged as key players in the antiviral response. Shortly, TRIM proteins were shown (i) to enhance pro-inflammatory cytokines production by interacting with pattern recognition receptors and downstream components of immune signaling pathways, (ii) to interfere with viral trafficking by interacting with the cytoskeleton, and (iii) to exhibit direct antiviral effects by targeting viral proteins for proteasomal degradation or inducing autophagy. This combination of actions underscores TRIMs as a potent innate defense system, but also makes them vulnerable to viral evasion strategies.

Epidemiological studies focusing on the association of exposure to perfluoroalkyl substances (PFAS) with cardiovascular disease (CVD) morbidity and mortality are limited, with inconsistent findings. This register-based study aimed to investigate the associations between exposure to PFAS and the risk of CVD morbidity and mortality in a Swedish population exposed to PFAS, dominated by perfluorohexane sulfonic acid (PFHxS) and perfluorooctane sulfonic acid (PFOS), through drinking water for decades. The study included 46,553 individuals aged ≥30 who lived in Ronneby (1985-2013). Individual exposure status was evaluated based on yearly residential address and categorized into 'ever-high' and 'never-high'. Incident CVD morbidity (acute myocardial infarction [AMI], ischemic [IS] and hemorrhagic stroke [HS]), and CVD mortality were retrieved from national registries. Cox proportional hazards models estimated hazard ratios (HR). Further stratified analyses were performed by calendar year, sex and age (<50, 50-75, >75 years). Elevated risks were found for AMI (HR 1.10, 95% confidence interval 1.01-1.19), IS (1.10, 1.00-1.22), HS (1.28, 1.03-1.59), and CVD mortality (1.15, 1.08-1.23) among individuals who had lived in the area with PFAS contaminated drinking water. Females showed higher risks for AMI and CVD mortality, while the risk of HS was higher among men. Stronger associations between PFAS and AMI and HS were observed in the age group 50-75 years. For PFAS-related CVD mortality, the point estimates increased with age though no significant interaction was observed. Our study suggests an association between high-level PFAS exposure and elevated risk of CVD morbidity and mortality.

The tripartite motif (TRIM) or RBCC proteins are characterized by the TRIM composed of a RING finger, B-box and coiled-coil domains. TRIM proteins often play roles in the post-translational protein modification, including ubiquitylation and other ubiquitin-like modifications. Evidence has accumulated in regard to the contribution of TRIM proteins to diverse cellular processes, including such as cell cycle progression, apoptosis, immunity and transcriptional regulation. In particular, some of the TRIM proteins have been characterized to exert oncogenic or tumour suppressor-like functions depending on the context. A recent report by Inoue and his colleagues has revealed that Terf/TRIM17 stimulates the degradation of a kinetochore protein ZWINT and regulates the proliferation of breast cancer cells. Terf has also been paid attention as a factor promoting neuronal apoptosis, by degrading a Bcl2-like anti-apoptotic protein Mcl-1. Like aircraft trim tabs, TRIM proteins trim the balance of homoeostasis by modulating various biological pathways through protein-protein interactions.

Dual role of TRIM E3-ligases in hepatocellular carcinoma: Mechanistic insights and therapeutic perspectives.

BackgroundThe tripartite motif (TRIM) proteins have been reported to play crucial roles in various malignancies. However, the clinical significance of TRIM proteins in colorectal cancer (CRC) remains controversial. This study aimed to evaluate the association between TRIM proteins and the clinicopathological features and survival outcomes in patients with CRC.MethodsWe performed a meta-analysis to investigate whether TRIM is a prognostic factor in CRC. PubMed, Embase, Web of Science, CNKI and Weipu databases were searched to identify eligible studies that evaluated the association between TRIM proteins and overall survival (OS), as well as the clinicopathological features of patients with CRC. Hazard ratios (HR) or odds ratios (OR) with 95% confidence interval (CI) were derived and pooled using a fixed-effects model.ResultsFrom inception to March 2023, we extracted study characteristics and prognostic data for each identified study. Twelve studies enrolling 1608 patients were eligible for inclusion. Data on OS and recurrence-free survival (RFS) were available for 12 and 2 studies, respectively. The pooled analysis results showed a significant correlation between the elevated TRIM proteins and shorter OS (HR = 2.42, 95% CI: 1.96–2.99) and worse RFS (HR = 2.51, 95% CI: 1.78–3.54) in patients with CRC. The combined ORs indicated that TRIM protein over-expression was significantly associated with advanced TNM stage (OR = 2.26, 95% CI: 1.25–4.10), deep tumor invasion (OR = 2.01, 95% CI: 1.04–3.88), lymph node metastasis (OR = 2.99, 95% CI: 2.19–4.09) and perineural invasion (OR = 1.95, 95% CI: 1.18–3.23).ConclusionsOur findings suggest that TRIM proteins can predict tumor progression and poor prognosis in CRC. Therefore, TRIM proteins may be promising therapeutic targets for patients with CRC.Graphical

The Tripartite motif (TRIM) protein family is classified among a cohort of E3 ubiquitin ligase families. A large percentage of TRIM proteins are E3 ubiquitin ligase active and take part in a number of cellular functions. By adding ubiquitin molecules to target proteins via a variety of techniques, it can change those proteins. The important role of the TRIM protein in controlling pattern recognition receptor signaling pathways and the defense mechanisms of mammals against viruses, with a focus on protecting the host from viral infections, has been clarified by recent study. In addition to triggering crucial cell-intrinsic defense mechanisms like autophagy and transcription-dependent antiviral responses, TRIM proteins can also exhibit direct antiviral effects by obstructing particular viral components via a variety of mechanisms. Regrettably, certain viruses have developed efficient mechanisms to evade the antiviral activities exerted by specific TRIM proteins, including SARS-CoV-2. Viruses has the capacity to exploit TRIMs and the ubiquitination process directly, hence enhancing the viral replication cycle and inducing heightened pathogenicity. In this article, I have delved into research that explores the molecular mechanisms responsible for the antiviral effects of TRIM proteins. Additionally, I have examined how TRIM proteins exert their influence on various viral entities, shedding light on their crucial role in the immune response against viral infections.

The tripartite motif (TRIM) protein family is a highly conserved group of E3 ligases with 77 members known in the human, most of which consist of a RING-finger domain, one or two B-box domains, and a coiled-coil domain. Generally, TRIM proteins function as E3 ligases to facilitate specific proteasomal degradation of target proteins. In addition, E3 ligase independent functions of TRIM protein were also reported. In hepatocellular carcinoma, expressions of TRIM proteins are both regulated by genetic and epigenetic mechanisms. TRIM proteins regulate multiple biological activities and signaling cascades. And TRIM proteins influence hallmarks of HCC. This review systematically demonstrates the versatile roles of TRIM proteins in HCC and helps us better understand the molecular mechanism of the development and progression of HCC.

BackgroundDiabetes, a chronic condition affecting various organs, is frequently associated with abnormal lipid metabolism, notably increased cholesterol and triglyceride levels. These lipid abnormalities are closely linked to the development and advancement of cardiovascular disease (CVD). Although regular physical activity (PA) has consistently shown benefits in reducing CVD risk in the general population, its precise influence on CVD risk among patients with diabetes remains uncertain, particularly regarding dose-response relationships.ObjectiveThis study aimed to summarize the evidence from prospective studies on the association between PA and CVD morbidity and mortality in individuals with diabetes and explore the optimal levels for public health recommendation.MethodsWe systematically reviewed prospective cohort studies in PubMed, Embase, and Web of Science up to December 2022, with inclusion criteria specifying the studies published in English and included adult participants diagnosed with diabetes. A random effects model was used to pool the relative risk (RR) with the corresponding 95% CI comparing the highest with the lowest PA categories in each study for qualitative evaluation. In addition, linear and spline regression analyses were used to estimate dose-response associations.ResultsThe meta-analysis included 12 prospective cohort studies, involving a total of 109,820 participants with diabetes. The combined results revealed that higher levels of PA were associated with a reduced risk of CVD. The RR of CVD for the highest compared with the lowest PA category was 0.62 (95% CI 0.51-0.73). In addition, there were 4 studies describing leisure-time PA, and the pooled RR was 0.68 (95% CI 0.52-0.83) for the highest versus the lowest activity. The linear regression model revealed that each 10 MET (metabolic equivalent of task)-hours per week of incrementally higher PA was associated with a 19% (95% CI 11.6-25.7) and a 6.9% (95% CI 4.5-9.3) reduction in CVD morbidity and mortality. Additionally, spline regression curves showed nonlinear relationships between PA levels and the risk of CVD and CVD mortality (both Pnonlinearity<.001), with a limited reduction in CVD risk and some further reduction in CVD mortality above 20 MET-hours per week of PA levels.ConclusionsFor patients with diabetes, especially type 2 diabetes, there was a dose-response relationship between increased PA and reduced risk of CVD morbidity and mortality. The observed PA threshold is consistent with the recommended level for the general population. Gradually moving from inactivity to a guideline-recommended PA level could therefore significantly reduce the burden of CVD in patients with diabetes.